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Corticosteroids
Inhalant, Systemic, and Topical Preparations


Depletions
Calcium
Mechanism

Corticosteroids increase renal calcium excretion and decrease intestinal calcium absorption (Gennari 1993; Lems et al. 1998). By altering normal calcium metabolism and reducing osteoblast activity, corticosteroids increase not only bone loss, but the risk for developing osteoporosis as well (Nielson et al. 1988; Reid and Ibbertson 1986).


Significance of Depletion

Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).


Replacement Therapy

Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (DrŁeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.


Dehydroepiandrosterone (DHEA)
Mechanism

Long-term treatment with corticosteroids suppresses DHEA production in post-menopausal women (Smith et al. 1994).


Significance of Depletion

Decreased plasma levels of DHEA have been linked to various pathologies such as certain cancers, cardiovascular disorders, inflammatory diseases, and type II diabetes mellitus (Hinson and Raven 1999).


Replacement Therapy

Daily doses of 50 mg in patients aged 40 to 70 years produced DHEA levels equivalent to those found in young adults within 2 weeks of initiation of replacement therapy (Morales et al. 1994). These levels were maintained for 3 months of the study and patients reported improvements in their general sense of physical and psychological well-being; no side effects were associated with DHEA therapy at this dose. It has been suggested that doses should not exceed 25 mg/day for women or 50 mg/day for men (Huppert et al. 2000). Long-term safety and efficacy of DHEA supplementation has not been established (Murray and Pizzorno 1998).


Magnesium
Mechanism

Corticosteroids reduce magnesium levels in serum and bone (Atkinson et al. 1998; Rolla et al. 1990; Simeckova et al. 1985).


Significance of Depletion

Magnesium deficiency affects calcium and vitamin D metabolism and is primarily associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.


Replacement Therapy

The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.


Melatonin
Mechanism

Corticosteroids may reduce nocturnal melatonin levels (Demisch et al. 1988).


Significance of Depletion

Alterations in melatonin levels have been associated with disturbances in the sleep-wake cycle and jet lag (Avery et al. 1998).


Replacement Therapy

Optimal doses for melatonin therapy have not been established (Avery et al. 1998). Commonly available doses range from 0.3 to 5 mg. Physiological blood levels are achieved with doses of 0.3 mg; higher doses (1 mg) result in supraphysiological levels of melatonin in the blood. The efficacy of melatonin supplementation is dependent upon the time of administration, as effects are related to circadian rhythms.

Note: Corticosteroid effects on the immune system may be modulated by melatonin (Rogers et al. 1997). In vitro, the combination of melatonin and corticosteroids produced significantly greater suppression of lymphocyte proliferation than corticosteroids alone.


Potassium
Mechanism

Corticosteroids enhance potassium excretion (Adam et al. 1984; Stanton et al. 1985).


Significance of Depletion

Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L.


Replacement Therapy

The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 2000). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.


Protein & Amino Acids
Mechanism

Corticosteroids may cause protein wasting (Garrel et al. 1988).


Significance of Depletion

Deficiencies of protein are characterized by compromised immune status, generalized decreases in function and strength, apathy, weight loss, increased susceptibility to infection, impaired wound healing, and growth retardation in children (Covington 1999). Severe depletion may be characterized by muscle wasting, deterioration in skin and hair, decreased heart rate, blood pressure, and body temperature.


Replacement Therapy

Nutritional repletion through dietary means is the preferred treatment approach in cases of protein depletion or deficiency (Covington 1999). Adopting a balanced diet consisting of high levels of calories, protein, vitamins, and minerals is one option available for the treatment of patients with depleted levels of protein. Oral or parenteral supplementation offers another therapeutic approach to restore nutritional status, maintain caloric intake, and achieve recommended dietary allowances for protein (generally 600 to 800 mg/kg protein) (Reeds and Beckett 1996).


Selenium
Mechanism

Corticosteroids may deplete selenium levels (Peretz et al. 1987).


Significance of Depletion

Selenium deficiency may lead to oxidative DNA damage (Ames 2000). Chronically low levels of this trace element are associated with pathologies such as cardiovascular disease, rheumatic disorders, muscle, and digestive problems (Navarro-Alarcon and Lopez-Martinez 2000). In addition, there may be a connection between depleted selenium levels and cancer, cirrhosis, and diabetes.


Replacement Therapy

The recommended dietary allowance (RDA) for selenium ranges from 0.70 to 3.50 mg/day (Ames 2000). Doses of 0.02 to 0.05 mg/day have been suggested to prevent selenium deficiency and its associated disorders (Navarro-Alarcon and Lopez-Martinez 2000). Optimal and toxic levels of this nutrient have not been established (Ames 2000). Selenium supplementation may play a role in cancer prevention, including prostate, breast, colon, and cervical carcinoma.


Vitamin B6 (Pyridoxine)
Mechanism

Corticosteroids may deplete vitamin B6 levels (Sur et al. 1993).


Significance of Depletion

Usually, vitamin B6 deficiency is accompanied by depletions of other B vitamins (National Research Council 1989). Signs and symptoms of low levels of this vitamin include epileptiform convulsions with abnormal EEG findings, dermatitis, anemia, weakness, mental confusion, irritability, nervousness, insomnia, and abnormal tryptophan metabolism (Covington 1999; National Research Council 1989; Wilson 1998). Depleted levels may increase the risk of colon and prostate cancers, heart disease, brain dysfunction, and birth defects (Ames 2000).


Replacement Therapy

Neuropathology resulting from vitamin B6 deficiency should be treated with doses of 50 to 200 mg/day (Covington 1999). Dietary deficiency usually responds to doses of 10 to 20 mg/day. Doses should be tailored to account for the patient's age, gender, clinical presentation, serum vitamin B6 levels, dietary habits, and medication regimen.


Vitamin B9 (Folic Acid)
Mechanism

Corticosteroids may deplete folic acid levels (Frequin et al. 1993).


Significance of Depletion

Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.


Replacement Therapy

The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, serum folate levels, age, gender, dietary habits, and medication regimen.


Vitamin B12 (Cobalamin)
Mechanism

Corticosteroids may deplete vitamin B12 levels (Frequin et al. 1993).


Significance of Depletion

Symptomatic vitamin B12 deficiency is rare because complications may appear only after the deficiency has existed for 10 to 15 years (Berger 1985; Carpentier et al. 1976). Low vitamin B12 levels could increase the risk of colon cancer, heart disease, brain dysfunction, birth defects, and irreversible neuropathy (Ames 2000; Covington 1999). Irritability, weakness, numbness, fatigue, glossitis, anorexia, headache, palpitations, and altered mental status, including personality and behavioral changes, are some of the signs and symptoms of vitamin B12 depletion (Covington 1999). Prolonged deficiency leads to pernicious or megaloblastic anemia that may be associated with leukopenia and thrombocytopenia.


Replacement Therapy

Doses of 25 to 250 mcg/day of vitamin B12 have been used to correct nutritional deficiency (Covington 1999). Oral doses between 500 to 1000 mcg/day have been recommended for the treatment of pernicious anemia (Carmel 2000). Replacement therapy should be based on the patient's individual needs, considering the clinical presentation, serum B12 levels, age, gender, dietary habits, and medication regimen.


Vitamin C (Ascorbic Acid)
Mechanism

Corticosteroids may inhibit cellular uptake of ascorbic acid and reduce concentrations in the aqueous humor and testicular tissues (Chowdhury and Kapil 1984; Levine and Pollard 1983; Mehra et al. 1982).


Significance of Depletion

Patients with depleted levels of vitamin C may present with anemia, icterus, edema, lethargy, fatigue, fever, ecchymoses, hypotension, convulsions, gum disorders, tooth loss, emotional changes, and perifollicular hyperkeratotic papules (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). In addition, they may exhibit signs of poor wound healing, increased susceptibility to infection, and markedly defective collagen synthesis. Severe deficiency results in scurvy, which is potentially fatal (Carr and Frei 1999; National Research Council 1989; Wilson 1998). Scurvy involves degenerative changes in capillaries, bone, and connective tissue, resulting in clinical symptoms that include weakness, joint tenderness and swelling, and spontaneous hemorrhages (Carr and Frei 1999; Covington 1999; National Research Council 1989; Wilson 1998). Patients with vitamin C deficiency may also be at increased risk of developing cataracts and heart disease (Ames 2000).


Replacement Therapy

Treatment of scurvy requires doses between 300 and 1000 mg/day for adults (Covington 1999). Other recommendations range from the recommended dietary allowance (RDA) of 60 mg to 2000 mg/day for adults (Carr and Frei 1999; Wilson 1998). One study proposes that no adult receive more than 1000 mg/day because higher doses could cause nausea and diarrhea (Ausman 1999). To minimize the possibility of gastric upset, buffered and sustained-release vitamin C preparations are recommended. Specific doses account for the patient's age, gender, overall health status, dietary habits, and medication regimen. Smokers must consume 2 to 3 times more vitamin C than non-smokers (Ames 2000).


Vitamin D
Mechanism

Corticosteroid therapy reduces serum 1,25-dihydroxyvitamin-D3 in children (Chesney et al. 1978).


Significance of Depletion

Because vitamin D is fat-soluble, prolonged periods of deficiency are required to produce symptoms (National Research Council 1989). While the long evolution is often asymptomatic (Rao 1999), depleted levels are characterized by inadequate mineralization of the bone, which could lead to rickets (in children) and osteomalacia (in adults) (Covington 1999; National Research Council 1989; Rao 1999). Other signs and symptoms of low levels of vitamin D include increased risk of fractures, osteoporosis, phosphaturia, hyperparathyroidism, chronic muscle weakness, hypovitaminosis D, bone pain, pseudofractures, waddling gait, or severe, chronic hypocalcemia (Holick et al. 1998; National Research Council 1989; Rao 1999; Vieth 1999). Subclinical vitamin D deficiency has been reported in postmenopausal women with osteoporosis (Rao 1999). The prevalence of vitamin D deficiency is more common in women, certain ethnic populations, and increases with age.


Replacement Therapy

Coadministration of vitamin D with calcium offsets the bone loss induced by chronic corticosteroid therapy (Frauman 1996; Hachulla and Cortet 1998; Weryha et al. 1998). Doses of vitamin D3 ranging from 1000 to 2000 IU/day or 25-OH-D3 ranging from 10 to 25 mcg/day have been used to treat vitamin D deficiency, which is characterized by low plasma levels of 25-OH-D3 (DrŁeke 1999). Other recommendations involve doses between 200 to 800 IU/day for adults (Rao 1999) and 50,000 IU/month for elderly patients with osteomalacia (Holick et al. 1998).


Zinc
Mechanism

Corticosteroids alter zinc metabolism and can cause depletion (Flynn et al. 1971; Fodor et al. 1975; Fontaine et al. 1991; Yunice, et al. 1981).


Significance of Depletion

Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000).


Replacement Therapy

Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.


Editorial Note

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.


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Copyright © 2000 Integrative Medicine Communications

This publication contains information relating to general principles of medical care that should not in any event be construed as specific instructions for individual patients. The publisher does not accept any responsibility for the accuracy of the information or the consequences arising from the application, use, or misuse of any of the information contained herein, including any injury and/or damage to any person or property as a matter of product liability, negligence, or otherwise. No warranty, expressed or implied, is made in regard to the contents of this material. No claims or endorsements are made for any drugs or compounds currently marketed or in investigative use. The reader is advised to check product information (including package inserts) for changes and new information regarding dosage, precautions, warnings, interactions, and contraindications before administering any drug, herb, or supplement discussed herein.